Assisted reproduction techniques include in vitro fertilization (IVF) and embryo transfer (ET). In IVF-ET, an oocyte is surgically removed, fertilized in vitro, and placed in the uterus or Fallopian tube of the same woman. In oocyte donation, the oocyte is recovered from a donor and after IVF it is transferred to an infertile recipient as in ET. This procedure requires synchronization between the donor and the recipient, which is generally achieved by administering steroid hormones to the recipient.
In regular IVF-ET, the treatments given to induce multiple follicle growth often lead to insufficient luteal function. Therefore progesterone supplementation is required for implantation and initial maintenance of pregnancy. OD-IVF-ET is performed in functionally agonadal females and thus there is no source of endogenous progesterone until the eighth to tenth week of pregnancy when the placenta assumes this function. Thus, progesterone supplementation is always required in OD-IVF-ET, and is required for longer periods of time.
Thus, exogenous progesterone supplementation is well-established in IVF and ET, as well as in the treatment of other ovulatory dysfunction. In addition, exogenous progesterone is an essential part of the hormonal replacement therapy required by the agonadal women to maintain pregnancy after oocyte donation.
The prior art methods of administration of exogenous progesterone to women undergoing assisted reproduction techniques suffer from significant disadvantages. Oral administration of progesterone is ineffective due to rapid clearance by the liver, resulting in low bioavailability in the circulation. Intramuscular administration is the most widely used form of progesterone replacement in agonadal women undergoing oocyte donation. This route, however, requires daily administration of high doses of progesterone (50 to 100 mg/day) for up to 100 days. The high serum concentration of progesterone and daily i.m. injections produce severe patient discomfort. Intravaginal progesterone administration has been used to prepare the endometrium for implantation, but may require insertion of progesterone tablets or suppositories into the vagina twice a day for approximately one hundred days.
Polysiloxane carriers have been used for delivery of progesterone as a contraceptive for lactating women (Croxatto et al., 1991, in "Female Contraception and Male Fertility Regulation. Advances in Gynecological and Obstetric Research Series", Reinnebaum et al., eds.) and for delivery of estradiol in postmenopausal women (Stumpf et al. (1982), J. Clin. Endocrinol. Metab., 58:208).
Simon et al. (1986), Fertility and Sterility, 46:619 disclose 17.beta.-estradiol and/or progesterone-impregnated polysiloxane vaginal rings and cylinders for endometrial priming in functionally agonadal women. The ring and cylinder system was used to achieve serum levels of 17.beta.-estradiol and progesterone within the normal range for an entire menstrual cycle. U.S. Pat. No. 4,816,257 discloses the use of polysiloxane rings containing 17.beta.-estradiol or 17.beta.-estradiol and progesterone to mimic normal steroid hormone levels in a functionally agonadal human female. To stimulate a normal human menstrual cycle, a sequence of rings and tampons of different formulations was required. Ring I, containing 200 mg 17.beta.-estradiol, was administered intravaginally on day one, and removed and replaced by Ring II, containing 400 mg 17.beta.-estradiol on day fourteen. On day nineteen, Ring III, containing 400 mg 17.beta.-estradiol and 1000 mg progesterone, was substituted for Ring II. One day twenty-five, Ring I was substituted for Ring III. On days fifteen to twenty-eight, a polysiloxane tampon containing 2000 mg progesterone was added to the regimen. Accordingly, the use of intravaginal rings to stimulate a normal menstrual cycle as disclosed by U.S. Pat. No. 4,816,257 is complex and inconvenient.
The present invention overcomes the deficiencies of the prior art by providing a convenient and efficient method of administering progesterone to a functionally agonadal human female undergoing assisted reproduction.